Cancer is the second leading cause of death in the United States. There is an acute need for cancer biomarkers that can be detected from clinically relevant samples and used for determining treatment regimes applicable to malignant diseases. Renal cell carcinoma (RCC) is the most lethal genitourinary cancer, accounting for approximately 209,000 new cancer occurrences and 102,000 deaths per year worldwide (Gupta et al, Cancer Treat Rev 34, 193 (2008); incorporated by reference herein.) Cure rates in RCC are modest since more than a quarter of patients have metastatic disease at presentation and patients treated surgically for localized cancers frequently relapse with metastatic disease (see Janzen et al, Urol Clin North Am 30, 843 (2003) and Lam et al, Curr Urol Rep 6, 7 (2005), both of which are incorporated by reference herein.)
RCC is histologically heterogeneous. While approximately 75% of RCC are clear cell carcinomas, other RCC cell types include papillary, chromophobe, sarcomatoid, collecting duct and medullary carcinomas (Bonsib, Clin J Am Soc Nephrol 4, 1998 (2009); incorporated by reference herein.) Inactivation of the VHL tumor suppressor gene is the most prevalent driver mutation, accounting for approximately 60% of all RCC tumors, occurring primarily in the clear cell subtype (Dalgliesh et al, Nature 463, 360 (2010) and Kim and Kaelin, J Clin Oncol 22, 4991 (2004); both of which are incorporated by reference herein.) Drugs that target VEGF and mTOR show clinical activity in unselected patients with metastatic RCC, though these responses are often variable and short-lived (Thomas et al, Nat Med 12, 122 (2006) and Rini and Atkins, Lancet Oncol 10, 992 (2009); both of which are incorporated by reference herein.)
Despite the fact that VHL-positive cancers account for approximately 40% of RCC, these patients suffer from a lack of biologically rational treatment options due to a paucity of identified molecular drivers. Furthermore, patients with papillary RCC and other “non-clear cell” RCC are often excluded from many registration trials (Motzer et al, J Clin Oncol 20, 2376 (2002) and Ronnen et al, Cancer 107, 2617 (2006); both of which are incorporated by reference herein), indicating that identification of predictive biomarkers that stratify patients for rational treatment strategies are needed.
The profound ability of the Bcr-Abl inhibitor imatinib to successfully treat CML supports such an approach and has led to the development of targeted therapies for other cancers (Demetri et al, N Engl J Med 347, 472 (2002); Druker et al, N Engl J Med 344, 1038 (2001) and Flaherty et al, N Engl J Med 363, 809 (2010); all of which are incorporated by reference herein.) But whereas targeted therapies are most effective in treating homogenous cancers driven by a single activating oncogene, they are much less effective in treating molecularly heterogeneous cancers such as RCC. Indeed, recent quantitative phosphoproteomic studies have revealed cancer to be a disease driven by aberrant networks rather than discrete signaling pathways (Huang et al, Proc Natl Acad Sci USA 104, 12867 (2007) and Stommel et al, Science 318, 287 (2007); both of which are incorporated by reference herein.) This observation is exemplified by Src kinase, which despite its pivotal role in tumor growth, angiogenesis and metastasis, is rarely mutated in cancer.